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Third international conference on systemic lupus erythematosus.

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SPECIAL ARTICLE
THIRD INTERNATIONAL CONFERENCE ON
SYSTEMIC LUPUS ERYTHEMATOSUS
PETER H. SCHUR
The Third International Conference on Systemic Lupus Erythematosus was held in London,
England, April 12-15, 1992. The meeting was hosted
(splendidly) by Dr. Graham Hughes. Almost 1,000
physicians and scientists from all over the world
attended. A summary of some of the highlights, compiled by session chairpersons, is presented herein.
of renal disease may result from different sequences of
DNA, histone, and anti-DNA deposition. Antiendothelial antibodies may contribute to this process.
IgG-N2 is the dominant idiotype found in renal biopsy
specimens.
Epidemiology
Normal human keratinocytes pertubated with
ultraviolet light or cultured in high concentrations of
estrogen synthesize ROBS-A first in the nucleus, then
in the cytoplasm, and then the Ro is expressed on the
plasma membrane. Thus, the kerotinocyte may become the target of (auto)immune reactions.
The need for standardization of diagnostic criteria for central nervous system (CNS) lupus and for
neurologic versus psychiatric events was stressed.
The high frequency of cognitive abnormalities detected by psychometric testing was noted repeatedly.
Some abnormalities correlate with serologic features:
visual spatial deficits with lymphocytotoxic antibodies, verbal memory deficits with antiphospholipid
antibodies, and development of subsequent CNS
events with neuronal antibodies. Abnormal findings on
single-photon emission computed tomography scanning and on magnetic resonance imaging were noted in
selected patients. MRLllpr mice were noted to develop behavioral abnormalities even before exhibiting
arthritis and lymphadenopathy. P ribosomal antigen
was detected on the surface of neuroblastoma cells in
culture, and this could (theoretically) be accessed by
anti-P antibodies.
Renal involvement
Heart and lung involvement
Immune complex-mediated lupus nephritis
may begin with histone binding of heparan sulfate in
the glomerular basement membrane, followed by deposition of DNA, and then anti-DNA. Different patterns
Pulmonary hypertension in SLE is associated
with a very poor prognosis. While pulmonary hypertension in SLE patients is non-thromboembolic in
most cases, in some it is associated with antiphospholipid antibodies. Some patients with acute hypoxemia
were described. Patients had serum complement acti-
The prevalence of systemic lupus erythematosus (SLE) is increased among Alaskan Indians and
among Asian Indians (in Great Britain), but not in
Chinese persons or in natives of Curagao, as compared
with Caucasians. The prevalence of SLE is quite low
among black Africans, in contrast to a high prevalence
among black Americans in the US and the Caribbean.
Skin involvement
From the Editor’s desk, Arthritis und Rheumutism.
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
Central nervous system involvement
THIRD INTERNATIONAL CONFERENCE ON SLE
vation and pulmonary vascular leukocyte aggregation.
Response to corticosteroid treatment was reported.
Valvular disease is common in SLE and may be
associated with antiphospholipid antibodies.
Pregnancy
In antiphospholipid antibody-positive SLE
mothers whose pregnancies ended in intrauterine fetal
death, the placentae showed findings consistent with
prolonged placental ischemia (i.e., fibrosis, thrombosis, infarct ion).
Neonatal lupus and childhood lupus
La was detected in fetal hearts at 7 weeks, and
Ro at I 1 weeks. Congenital complete heart block
(CCHB) was associated with maternal anti-Ro (52 kd)
and anti-La. Neonatal lupus rash was not associated
with any particular maternal antibody profile. No clear
guidelines for treatment of CCHB in the fetus were
agreed upon. The observation that children often have
more severe systemic illness and have a high frequency of renal disease was reaffirmed from centers
around the world.
Immunology
New Zealand black (NZB) mice with the
mutation had high-titer anti-DNA antibodies
and accelerated glomerulonephritis. T cells that help B
cells make anti-DNA were cloned from these mice; the
T cells have the phenotype CD4+, T cell receptor dulp,
Th2 cytokine. Ninety-two percent of SLE sera contain
a 78-kd protein (“Mx”), which can be induced in
mononuclear cells by interferon-a (IFNa). Urine, but
not serum, of SLE patients contains antibodies to
extracellular matrix proteins. SLE T cells have increased interleukin-2 (IL-2) messenger R N A (mRNA)
levels, and decreased IL-4 mRNA. These observations suggest that increased B cell activity and depressed cell-mediated immunity could be accounted
for by activation of type 2 CD4+ cells, or other T cell
subsets. SLE T cells may be down-regulated by transforming growth factor @. Serum levels of type I (p55)
and type I1 (p75) tumor necrosis factor (TNF) receptors are elevated, especially in active disease. While
there is little increase in serum/plasma levels of IL-6,
there is an increase in IL-6 receptors.
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Molecular biology
Antihistone 2A and antihistone 2B may develop
sooner than anti-DNA. Anti-DNA and anti-RNP generation are probably mostly antigen driven, while
anti-Ro may be driven by molecularly similar (“mimicry”) antigens. The idiotypes (Id) 16/6, 31, 8.12, F4,
and 9G4 were found in more than 50% of SLE patients
and in tissue lesions from many patients. Id are
encoded by V, germline genes. SLE could be induced
in mice by immunization with 16/6-Id anti-DNA; the
antiphospholipid antibody syndrome could be induced
in mice by immunization with anticardiolipin antibodies. The recurrence of shared idiotypes suggests that a
limited set of gene segments is used in autoantibodies.
Antibodies to heat shock proteins (HSP) are present in
low levels in patients with SLE, while hsp70 and hsp90
may be overexpressed on T cells in some patients,
especially those with neurologic disease. A search for
the role of HSP in SLE continues.
Antiphospholipid antibodies
The importance of &-glycoprotein (p,-GP) reacting with cardiolipin in determining antiphospholipid
reactivity was extended; &-GP has been cloned and
sequenced. The (NZB x BXSB)F, mouse develops
antiphospholipid antibody syndrome. Immunization of
animals with &-GP was shown to induce antiphospholipid antibody syndrome in one study, but not in
another.
Genetics
HLA-DR3 positive SLE patients produce high
levels of TNF and have a lower frequency of nephritis;
DR2 positive patients produce little TNF and have a
higher incidence of nephritis. TNF accelerates nephritis in MRLllpr mice, and prolongs survival and delays
renal disease in NZB x NZW mice. Local production
of TNF (both strains produce it) may have a more
important role. One-third of patients with C4A protein
deficiency have DR3 and a C4A gene deletion. In C4A
null-associated lupus, there is a lower frequency of
anti-DNA, renal disease, and complement consumption. C4A null-associated SLE may be due to the
B8;DR3 haplotype. DR6 may protect against the development of nephritis. Anti-Ro and anti-La were
associated most closely with DQ genes.
SCHUR
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Sex hormones
Levels of aromatase are increased in skin lesions of patients with SLE. Blood prolactin levels
correlate with disease activity in mice and humans,
and these levels may be influenced (with concomitant
improvement of disease activity in animals) by treatment with bromocriptine. The anti-estrogen, tamoxifen, may be of benefit. Women with SLE have antiovary antibodies, and male patients have antitesticular antibodies. Clinical improvement may occur
with menopause.
Treatment
Possible new biologic agents for the treatment
of S L E were reviewed, including intravenous IgG
(thrombocytopenia responds, nephritis worsens), immunoabsorption (treatment needs to be repeated, may
become expensive), photopheresis, monoclonal antibodies, IL-2 receptor, and T cell receptor. Measurement of glucocorticoid receptor density may represent
an improved gauge for determination of proper steroid
dosage. In one study, cyclosporine was of benefit in
nephrotic syndrome. Antibodies to double-stranded
DNA were noted to develop in chronic lymphocytic
leukemia patients treated with IFNa. I F N a should
therefore be used with great caution in patients with
SLE.
Summary
A Fourth International Conference on Systemic
Lupus Erythematosus will be held in Jerusalem in
March 1995. We look forward to a better understanding of the molecular, genetic, immunologic, and clinical aspects of the disease and trust that this knowledge
will result in improved treatment.
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